The availability of PET as a tool for research in biology and medicine has expanded significantly in the past decade along with the sophistication of the instrumentation and the diversity of radiotracers which are being applied to specific problems in biology and medicine. The major scientific goal of this proposal is to address the key research issues in radiotracer chemistry and biochemistry which are required to accelerate the application of PET to new problems in biology and medicine. Specific aims include high level economical production of fluorine-18 and carbon-11 on medical cyclotrons, mechanistic and synthetic chemistry as it relates to radiotracer synthesis and analytical control, radiotracer design and biochemistry as a linkage between PET measurements and the physiological process itself and automation of radiotracer production, and analysis including the use of knowledge-based artificial intelligence for rapid diagnosis of problems. New radiotracers for assessing degree of malignancy in brain tumors by measuring functional ornithine decarboxylase activity (using 5-11C-ornithine) will be developed. A new approach to radiotracer design, the use of 11C-labeled suicide inhibitors of monoamine oxidase (MAO) to assess functional enzyme activity initiated during this grant period will be further exploited. The introduction of a major new thrust, the use of PET as a scientific tool in pharmaceutical research and development for new therapeutic drugs, will begin with the synthesis of positron emitter labeled drugs such as (11C) midazolam, a recently introduced benzodiazepine receptor active drug used in pre-anesthetic sedation. Because of the growing importance of fluorine-18 for high resolution PET studies, and for measuring biological processes over a time interval of several hours, new approaches to its economical production in high yield on medical cyclotrons employing reusable solid 18O-targets and its efficient incorporation into a wide spectrum of 18F-tracers through the general synthesis of 3-(18F) fluoropropyl derivatives of biologically active compounds will be developed. This research which is motivated by the use of PET compounds will be developed. This research which is motivated by the use of PET to address important scientific and medical issues will also be undertaken with a view to the economical supply of radiotracers from a central medical cyclotron-chemistry resource to satellite clinical PET facilities and to the pharmaceutical industry.